The candidate Wilms' tumour gene is involved in genitourinary development

Pritchard‐Jones, Kathy; Fleming, Stewart; Davidson, Duncan; Bickmore, Wendy A.; Porteous, David J.; Gosden, Christine; Bard, Jonathan; Buckler, Alan; Pelletier, Jerry; Housman, David E.; Heyningen, Veronica van; Hastie, Nicholas D.

doi:10.1038/346194a0

Cited by 792 publications

(428 citation statements)

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“…The wt1 gene shows a very de®ned spatial and temporal expression in the developing urogenital system, and is essential for mesenchymal-epithelial transitions in this system (Pritchard-Jones et al, 1990;Pelletier et al, 1991c). In addition, wt1 is also expressed in the hematopoietic system, although its role in this system is not de®ned (Reddy and Licht, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…The wt1 gene is expressed in a very de®ned spatialtemporal manner being expressed mainly in the kidney, gonads, spleen, and mesothelium (Pritchard-Jones et al, 1990;Pelletier et al, 1991c). In the developing kidney, the gene is expressed during the mesenchymal to epithelial transition, suggesting that wt1 plays a critical role during this developmental step (PritchardJones et al, 1990;Pelletier et al, 1991c).…”

Section: Introductionmentioning

confidence: 99%

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Activation of the wt1 Wilms' tumor suppressor gene by NF-κB

1998

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The Wilm's tumor suppressor gene, wt1, is expressed in a very de®ned spatial-temporal fashion and plays a key role in development of the urogenital system. Transacting factors governing wt1 expression are poorly de®ned. The presence of putative kB binding sites within the wt1 gene prompted us to investigate whether members of the NF-kB/Rel family of transcription factors are involved in regulating wt1 expression. In transient transfection assays, ectopic expression of p50 and p65 subunits of NF-kB stimulated wt1 promoter activity 10 ± 30-fold. Deletion mutagenesis revealed that NF-kB responsiveness is mediated by a short DNA fragment located within promoter proximal sequences of the major transcription start site. Two kB-binding sites are present in this region and form speci®c complexes with puri®ed NF-kB proteins, as revealed by electrophoretic mobility gel shift assays. Ectopic expression of p50 and p65 resulted in increased transcription of the endogenous wt1 gene, as revealed by nuclear run-on experiments. Taken together, these results indicate that members of the NF-kB/Rel family are important for activating expression of wt1 and reside upstream of the regulatory cascade leading to wt1 activation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation of the wt1 Wilms' tumor suppressor gene by NF-κB

1998

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“…In contrast to normal mature hematopoietic cells, cells of acute leukemia often express high levels of the zinc-®nger containing transcription factor Wilms' Tumor gene 1 (WT1) (Miwa et al, 1992). The WT1 protein is mainly expressed in developing kidney, testis, ovary and spleen, indicating that it is involved in the differentiation processes of certain tissues (Call et al, 1990;Gessler et al, 1990;Pritchard-Jones et al, 1990). Moreover, WT1 knock-out mice die before birth with failure of kidney and gonadal development (Kreidberg et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Constitutive expression of the Wilms' tumor gene (WT1) in the leukemic cell line U937 blocks parts of the differentiation program

et al. 1998

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The Wilms tumor gene, WT1, encodes a zinc-®nger DNA binding protein which is thought to function as a tissue speci®c transcription factor, regulating cell growth and di erentiation. High expression of WT1 has been detected in a range of acute leukemias. To elucidate a role for WT1 in leukemogenesis, we transfected the monoblastic cell line U937, which lacks detectable levels of endogenous WT1, with two isoforms of WT1. We showed that, in contrast to U937 control cells, cells constitutively expressing either of the isoforms, WT1(7KTS) or WT1(+KTS), did not respond to di erentiation induction by retinoic acid or vitamin D3, as judged by the capacity to reduce nitro blue tetrazolium and morphology. Although U937 cells expressing WT1 were hampered in their ability to di erentiate on incubation with retinoic acid and vitamin D3, the induced G1/G0-accumulation was similar to di erentiating control cells treated with inducers. Furthermore, distinct e ects on the maturation process were indicated by downregulation of the myeloid cell surface makers CD13 and CD15, while the upregulation of CD14 and CD11c on WT1 transfected cells was similar to control cells upon incubation with retinoic acid and vitamin D3. Taken together our results demonstrate that a constitutive expression of WT1 in the leukemic cell line U937 leads to impairment of di erentiation responses, indicating that a high expression of WT1 can contribute to the di erentiation block of acute leukemia.

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“…WT1 is upregulated in expression at the point of the mesenchyme to epithelial transition. 16 The frequent observation of persistent blastema and unsuccessful attempts at epithelialization in Wilms' tumors implicate WT1 in the same pathway. This was confirmed recently by the use of siRNAmediated knockdown of gene expression in kidney organ culture.…”

Section: Discussionmentioning

confidence: 99%